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Purinergic system involvement in the behavioral consequences of stress and in the antidepressant mechanism of action

Grant number: 13/01737-7
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): November 01, 2013
Effective date (End): April 08, 2017
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Sâmia Regiane Lourenço Joca
Grantee:Deidiane Elisa Ribeiro
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Depression is a heterogeneous syndrome with complex and variable symptoms. Therefore, this disorder requires a careful diagnosis and appropriate treatment. However, antidepressants available for clinical use are ineffective in about 45% of patients with depression. Thus, the search for new pharmacological targets for the depression treatment is necessary. The purinergic receptors are widely expressed in the central nervous system and are involved in pathological and physiological functions. Recent studies have indicated the purinergic system possible involvement in the depression neurobiology. According with this studies, P2X7 receptors knockout mice have antidepressant-like phenotype and the purinergic receptor antagonist treatment is capable of inducing antidepressant-like effect. The ATP interaction with P2X presynaptic receptors results in increased intracellular calcium concentration which can induce vesicular release of glutamate. Glutamate can interact with postsynaptic NMDA receptors resulting in Ca2+ influx, activation of neuronal nitric oxide synthase (nNOS) and subsequent synthesis of nitric oxide (NO). Moreover, activation of postsynaptic P2X receptors results in increased Ca2+ influx and could induce activation of nNOS and NO synthesis directly. NO seems to be able to decrease the secretion of brain-derived neurotrophic factor (BDNF). BDNF levels appear to be reduced in patients with depression and are restored by antidepressant treatment. Since treatment with glutamate receptor antagonists or inhibitors of NO synthesis is able to induce antidepressant-like effect in animals, the present study aim to investigate the hypothesis that systemic administration of P2 receptor antagonist in animals submitted to the model of learned helplessness is capable of inducing antidepressant-like effect by decreasing the synthesis of NO in the hippocampus. Moreover, it is intended to investigate whether BDNF-TrkB pathway signaling facilitation is also involved in this drug antidepressant-like effect. Besides, is intended to investigate the purinergic system involvement in drugs effect. For this aim, the effect of stress and antidepressant treatment on the expression of purinergic receptors in the hippocampus will be determined.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
RIBEIRO, DEIDIANE E.; MUELLER, HEIDI K.; ELFVING, BETINA; ESKELUND, AMANDA; JOCA, SAMIA R. L.; WEGENER, GREGERS. Antidepressant-like effect induced by P2X7 receptor blockade in FSL rats is associated with BDNF signalling activation. JOURNAL OF PSYCHOPHARMACOLOGY, v. 33, n. 11, p. 1436-1446, NOV 2019. Web of Science Citations: 1.
RIBEIRO, DEIDIANE ELISA; CASAROTTO, PLINIO C.; STAQUINI, LAURA; PINTO E SILVA, MARIA AUGUSTA; BIOJONE, CAROLINE; WEGENER, GREGERS; JOCA, SAMIA. Reduced P2X receptor levels are associated with antidepressant effect in the learned helplessness model. PeerJ, v. 7, OCT 21 2019. Web of Science Citations: 0.
GODOY, LIVEA DORNELA; UMEOKA, EDUARDO H. L.; RIBEIRO, DEIDIANE ELISA; SANTOS, VICTOR RODRIGUES; ANTUNES-RODRIGUES, JOSE; LOURENCO JOCA, SAMIA REGIANE; GARCIA-CAIRASCO, NORBERTO. Multimodal early-life stress induces biological changes associated to psychopathologies. Hormones and Behavior, v. 100, p. 69-80, APR 2018. Web of Science Citations: 3.

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